Toxicity andMonitoring ofImmunosuppressiveTherapy Used inSystemic AutoimmuneDiseases

Keith C. Meyer, MD, MS, FCCPa,*,Catherine Decker, PharmD, AE-Cb,Robert Baughman, MD, FCCPc

KEYWORDS

� Immunosuppressive drugs � Adverse drug reactions� Connective tissue disease � Autoimmunity

In addition to the extrapulmonary disease manifes-tations and nonpulmonary organ system dysfunc-tion patterns that characterize specific forms ofconnective tissue disease (CTD), systemic autoim-mune disorders frequently involve the lung andcan lead to pulmonary fibrosis and/or pulmonaryhypertension or vasculitic hemorrhage. Cortico-steroids continue to be a mainstay of therapy,especially for acute flares of lung disease.However, other agents may be more effective inachieving remission and stability of the diseaseand allow corticosteroid dosages to be reducedto low levels, particularly in chronic phases of thedisease (Table 1).

Corticosteroids and nonsteroidal antiinflamma-tory drugs (NSAIDs), once primary therapies formany of the systemic autoimmune diseasessuch as rheumatoid arthritis (RA), were eventuallysupplanted in the 1980s and 1990s by antimetab-olite/cytotoxic agents. These disease-modifying

a Section of Allergy, Pulmonary and Critical Care MediciSchool of Medicine and Public Health, 600 Highland Aveb Department of Pharmacy, University of Wisconsin HoPharmacy, Adult Pulmonary Clinic, 600 Highland Avenuec Interstitial Lung Disease and Sarcoidosis Clinic, DeparCenter, Eden Avenue & Albert Sabin Way, Cincinnati, OH* Corresponding author.E-mail address: kcm@medicine.wisc.edu

Clin Chest Med 31 (2010) 565–588doi:10.1016/j.ccm.2010.05.0060272-5231/10/$ – see front matter ª 2010 Elsevier Inc. All

antirheumatic drugs can be steroid-sparing andinduce/maintain remission. In the 1990s andbeyond, biologic agents have come into wide-spread use1 and have revolutionized the treat-ment of many forms of systemic autoimmunedisease. However, all of these agents, nonbio-logic and biologic, can cause serious adversereactions that can be life threatening. Knowledgeof their potential toxicities and interactions withother drugs combined with the adoption ofa systematic approach to monitoring therapycan minimize the likelihood that a life-threatening reaction occurs.

This article provides an overview of the potentialmajor toxicities (Table 2) and drug-drug interac-tions of the various drugs used to treat systemicautoimmune disorders and recommends anapproach to monitoring for adverse reactions tothese agents. The article focuses predominantlyon antimetabolite/cytotoxic (nonbiologic) and

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Table 1Summary of mechanism of action, routes of administration, and metabolism

Drug Class Specific Drug Mechanism of Action

Route of Administ tion

Metabolism and EliminationIV Oral Other

Corticosteroid Prednisone ormethylprednisolone

� Glucorticoid analog; suppresses inflammatorymediator production and immune effector cells

� Promotes T-lymphocyte apoptosis

1 1 � Prednisone converted to active formof drug (prenisolone)

� Excreted in the urine

Anti-TNFAgents

Adalimumab � Monoclonal antibody that binds TNF-a� Blocks interaction of TNF-a with p55

and p75 cell surface receptors

SC � Systemic clearance w 12 ml/h� Terminal half-life w 2 weeks.� No kinetic info for renal/hepatic disorder

Etanercept � Soluble form of p75 TNF receptor; inhibitsbinding of TNF-a and TNF-b to cell surfacereceptors

� Modulates adhesion molecules expression

SC � Speculated to be metabolized throughthe RES system

Infliximab � Monoclonal antibody that binds TNF-a� Blocks interaction of TNF-a with p55

and p75 cell surface receptors

1 � Elimination by unspecified proteases (?)� Systemic clearance w11ml/h� Linear pharmacokinetics are suspected

Antimetabolite/CytotoxicAgents

AZA � Antagonizes purine metabolism and mayinhibit synthesis of DNA, RNA and proteins;interferes with cellular metabolism and mitosis

1 1 � Metabolism by systemic and hepatic routes� Elimination via systemic, hepatic,

and renal pathwaysCyclophosphamide � Nitrogen mustardlike alkylating agent

� Cross-links DNA and RNA strands, thusinhibiting cell functions and protein synthesis

1 1 � Metabolized extensively by liver� Renal (5%–25% unchanged in urine)

and systemic eliminationLeflunomide � Inhibits dihydrooratate dehydrogenase

� May inhibit T-cell pyrimidine biosynthesis1 � Metabolized by liver and gut wall

� Undergoes enterohepatic recirculationEliminated renally and via total body clearance

MTX � Reversible inhibition of dihydrofolatereductase

1 1 SCIM

� Metabolized via liver, intracellularmetabolism, and gut.

� Excreted via kidneys, bile and fecesMPA derivatives � Blockade of de novo guanosine nucleotide

synthesis impairs NA synthesis and inhibitsT- and B-lymphocyte proliferative responses

1 1 � Extensive liver metabolism� Eliminated via the kidney

Other Chloroquines � Antimalarial agents� Immunosuppressant mechanism unclear

1 � Metabolized by liver� Eliminated primarily via kidney

Imatinib mesylate � Protein-tyrosine kinase inhibitor 1 � Metabolized by liver P-450 enzymes (CYP3A4,CYP1A2, CYP2D6, CYP2C9, and CYP2C19)

� Eliminated via feces (68%) and kidney (13%)Rituximab � Promotes B-cell lysis by binding to CD-20

antigen on B lymphocytes1 � Excretion pathway is uncertain

� May undergo phagocytosis andcatabolism via RES

Abbreviations: IM, intramuscular; NA, nucleic acid; RES, reticuloendothelial system; SC, subcutaneous; TNF, tumor necrosis factor.

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Table 2Adverse drug reactions (ADR) associated with immunosuppressant agent administration

Drug Class Specific Drug

InjectionSite/InfusionReactions Infection

Bone-marrowSuppression

NeurologicEffects

GIEffects

HepaticEffects

Renal/Genitourina yEffects

Cardio-vascularEffects

Dyslipi-demia

Mali-gnancy

PulmonaryToxicity

OcularToxicity

SkinReactions/Rash

Corticosteroids PrednisoneMethylprednisolone

1 1 � 1 ? � � ? 1 1

Anti-TNFagents

Adalimumab 1 1 � 1 � � 1 1 1 ? � 1Etanercept 1 1 � 1 1 � ? ? � 1Infliximab � 1 � � � � ? 1 ? � � 1

Antimetabolite/cytotoxicagents

AZA ? 1 1 ? 11 11 ? ? 1 1 ? �Cyclophosphamide ? 1 11 1 � 11 1 1 1 � 1Leflunomide NA 1 1 1 1 1 11 1 ? 1MTX ? 1 1 1 11 11 1 1 ? 1 1 1MPA derivatives 1 1 1 1 1 11 11 11 ? 1 1 1

Other agents Chloroquine/hydroxychloroquine

1 ? 1 1 1 1 1 1

Imatinib mesylate NA 1 1 1 1 1 1 1 1 11 1Rituximab 1 1 � 1 11 � � 1 ? � ? 1

Abbreviations: Bblank, no medication-associated ADR reported; NA, not applicable; �, ADR suspected to be associate with medication use, yet is infrequent; 1, ADR associated withmedication use exists ; 11, ADR associated with medication use exists and is noted in greater frequency than 1; ?, u known association of ADR with medication use.

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biologic (immunomodulatory/antibody-based)agents.

SPECIFIC AGENTSCorticosteroids

Systemic corticosteroids are valuable in treatingacute disease but may have serious side effects.2

A myriad of complications (Box 1) may and oftendo occur when high doses and/or prolongedtherapy with corticosteroids are prescribed.Some of these complications can be controlledand even prevented, such as fluid retention andweight gain. Steroid-sparing agents may allowcontrol of disease processes and thereby mini-mize systemic corticosteroid administration andassociated adverse effects. Patients should beeducated about potential side effects andinformed of strategies that may limit some of theadverse effects of corticosteroids. In addition,patients should be monitored for the onset ofsystemic hypertension, excessive weight gain/fluid retention, gastrointestinal (GI) symptoms,increased blood glucose, osteoporosis, hip pain,and dyslipidemia (Table 3). A diet and regularaerobic exercise that diminishes risk for heartdisease should be followed along with periodicmonitoring of a peripheral blood lipid profile. Abone mineral density scan should be obtained atbaseline and at subsequent periodic intervals,

Box 1Complications of corticosteroid therapy

Osteopenia/osteoporosis

Systemic hypertension

Weight gain

Glucose intolerance/diabetes

Dyslipidemia

Accelerated atherosclerosis

Myopathy

Infection

Avascular necrosis of bone

Cataracts

Glaucoma

Atrophy of skin

Adverse psychological effects

Disrupted sleep

Growth retardation

Cushingoid changes

Dyspepsia

and vitamin D levels should be obtained (andtestosterone levels in men). Vitamin D and supple-mental calcium should be given if indicated.

BIOLOGIC AGENTSAntitumor Necrosis Factor Agents

Biologic agents directed against tumor necrosisfactor a (TNF-a) have proved successful in treatingvarious manifestations of RA. These include theTNF receptor antagonist etanercept3 as well asthe chimeric, humanized monoclonal anti-TNFantibody infliximab4 and the humanized mono-clonal antibodies adalimumab5 and golimumab.6

Etanercept is a soluble, fully human recombinantform of the p75 tumor necrosis factor receptorfused with the Fc portion of IgG1. In contrast tothe anti-TNF antibodies, etanercept acts bybinding to endogenous-soluble and membrane-bound TNF, thereby preventing its interactionwith TNF receptors and rendering it biologicallyinactive.7 In addition to treatment of RA, anti-TNFantibodies also have regulatory approval for thetreatment of psoriasis, ankylosing spondylitis,ulcerative colitis, and Crohn disease.8

In the past 10 years, anti-TNF agents have beengiven to more than a million patients, and severalguidelines for monitoring their use have beenproposed.9–11 Potential toxicities linked to theadministration of these drugs include infection,infusion or injection reactions, worsened conges-tive heart failure (CHF), demyelination syndromes,lupus-like reactions, and increased risk of malig-nancy.12–16

InfliximabAn estimated 2-fold risk of infection is the mostcommon adverse event associated with infliximabuse.17,18 Most upper respiratory tract or urinarytract infections have not been serious, but case-controlled studies have suggested an increasedincidence of opportunistic infections.17 Althoughno prospective, randomized data exist, somereports have suggested that the risk of developingtuberculosis may be greater with infliximab thanwith other anti-TNF agents,19–21 and tuberculosisinfections are also more likely to beextrapulmonary.19,21,22

Existent data are not sufficient to determine iflymphoma or nonlymphomatous malignanciesare increased.17 Hepatosplenic T-cell lymphomashave been reported in rare postmarketing reports,particularly in adolescent23 and young adultpatients with Crohn disease,24 and have exclu-sively occurred in patients concomitantly treatedwith azathioprine (AZA) or 6-mercaptopurine.

Table 3Summary of monitoring precautions

Drug Class Specific Drug Recommended Precautions and Monitoring

Corticosteroids Methylprednisolone � Assess diabetes risk, blood glucose, BMD at baselinePrednisone � Periodically monitor: blood glucose, blood pressure,

body weight, BMD, weight, muscle strength(proximal), mental status

Anti-TNF agents Adalimumab � Assess tuberculosis risk; tuberculin skin test and chestradiograph before therapy

Etanercept � Avoid use during active infection (eg, viral hepatitis)Infliximab � Hepatitis serology before therapy if increased risk of

infection; monitor for viral hepatitis reactivation inpatients with history of viral hepatitis or chroniccarrier state

Antimetabolite/cytotoxic agents

AZA � Dose reduction (eg, 25%–35%) if coadministeredwith allopurinol

� Monitor CBC with platelets and hepatic functionCyclophosphamide � CBC with platelets and differential cell count

at baseline� Monitor CBC, renal function, and urinalysis at least

twice monthly� Increase fluid intake on the day of therapy

(eg, 2 L per 24 h)� If hematuria occurs, evaluate for cause

Leflunomide � Screen for use of alcohol and viral hepatitis beforeonset of therapy

� Perform periodic assessment of CBC and liverfunction

MTX � Screen for use of alcohol and viral hepatitis beforeonset of therapy

� Provide folic acid supplementation� Perform periodic assessment of CBC (eg, monthly)

and liver function (eg, every 1–2 months)MPA derivatives � Monitor CBC periodically

� Monitor for gastrointestinal toxicityand neurotoxicity

� Avoid concomitant use of AZA

Other agents Chloroquine/hydroxychloroquine

� Monitor for ocular toxicity every 6–12 months� Periodic therapy during prolonged therapy

Imatinib mesylate � CBC weekly for first month of therapy; biweeklyfor second month, then periodically

� Liver function at baseline and at subsequent monthlyintervals

Rituximab � Monitor for infusion reactions(eg, cardiac rhythm disturbance)

� Monitor CBC and liver function

Toxicity and Monitoring of Immunosuppressive Therapy 569

Caution has been recommended in treatingpatients with a previous history of malignancy.25

A large, placebo-controlled trial of infliximab(5–10 mg/kg) in New York Heart Classification IIIor IV heart failure (ATTACH trial) showed nobenefit, and the risk of all-cause death or hospi-talization for heart failure was increased inpatients treated with infliximab (10 mg/kg).26 Inaddition, numerous postmarketing reports havedescribed worsening heart failure during

therapy.17 Recent reports suggest that infliximabtherapy can alter plasma lipids with increases intotal cholesterol and high-density lipoprotein,27,28

but the potential effect of infliximab therapy onatherogenesis is not clear.

Central nervous system events, including demy-elination disorders, have been reported sporadi-cally with TNF inhibitors.16,17,29 Rare cases ofsystemic lupus erythematosus-like syndromeshave been reported with anti-TNF therapy and

Meyer et al570

generally resolved within 6 weeks to 14 months ofdiscontinuation.25 In addition, hematological sideeffects such as leukopenia, neutropenia, thrombo-cytopenia, and pancytopenia have been occasion-ally reported.17 Severe hepatic reactions have alsobeen reported, and infliximab has been associatedwith reactivation of hepatitis B virus infection.24,30

AdalimumabAs with infliximab, adalimumab administration hasbeen associated with increased infection risk,especially tuberculosis,31 and serious infectionshave been associated with the use of adalimu-mab.32,33 However, the rate of serious infectionwas not statistically different from that encoun-tered in the comparator groups in 2 differenttrials.34,35 Adalimumab has been associated witha cluster of cases of Legionella pneumophila pneu-monia,36 and Pneumocystis jiroveci pneumoniaoccurred in a patient receiving adalimumab.37

Autoimmune disease seems to be induced byanti-TNF agents.13 In a detailed analysis of a largecohort of cases, 15 of 92 cases of a lupuslike reac-tion were treated with adalimumab13 and vasculitiswas in reported in 113 patients, 5 of whom weretreated with adalimumab. Nervous system events,including demyelination disorders, have beensporadically reported in patients treated withadalimumab.17,38

EtanerceptSerious injection site reactions can occur, andinjection site-associated necrotizing fasciitis hasbeen reported.39 Reactivation of latent tubercu-losis has been associated with TNF inhibitors,40

but it is not clear whether etanercept therapyincreases the risk more than the already increasedrisk of reactivation tuberculosis for patients withRA.41 In the available case series, infection withtuberculosis was extrapulmonary in half the cases,suggesting that etanercept does have a role ininhibiting control of this organism.41 However,the soluble TNF fusion receptors, which includeetanercept, seem to be associated with less riskof reactivation TB than the monoclonal TNF antag-onists, infliximab and adalimumab.41 It is not clearwhether etanercept has adverse effects if given topatients with CHF, but there have been casereports of de novo cardiac failure or worsening ofpreexisting cardiac dysfunction in patients treatedwith etanercept.42 Sarcoidosislike reactions havebeen reported, and seem to occur more frequentlywith etanercept than with other anti-TNF agents.43

Non-Hodgkin lymphomas have been reported inpatients treated with etanercept, including severalin whom the lymphoma regressed followingcessation of the drug.44,45 However, the baseline

incidence of lymphoma is increased in individualswith the chronic inflammatory diseases that aretreated with etanercept. In addition, a large studyon patients with RA did not show a statisticallysignificant increased incidence of lymphoma inindividuals who received etanercept.46 Demyelin-ation syndromes have not been clearly linked toetanercept.

Monitoring therapy with anti-TNF agentsEarly observations of the association of anti-TNFtherapy and tuberculosis infection noted thatpatients receiving infliximab had a higher riskthan those receiving etanercept. Most cases ap-peared to be reactivated latent tuberculosis ratherthan new infection.20,47 These observations led toan intense effort to screen for latent tuberculosis,and this screening effort has been successful inreducing the rate of active tuberculosis in patientsreceiving anti-TNF therapy. In one registry of 5198patients treated with a TNF antagonist, 15 cases ofactive tuberculosis were noted. The calculatedrate of active tuberculosis was 172 per 100,000patient-years.48 Recommendations for monitoringwere fully followed in about half of the patients inthis study, and the risk for developing active tuber-culosis was 7 times higher for those who did notundergo the proposed monitoring. The mostcommon reason for failing to comply with therecommendations was the failure to performa tuberculin skin test.48 Although these resultssupport the value of a tuberculin skin test to detectlatent tuberculosis, patients receiving immuno-suppressive drugs may become anergic.Antigen-specific testing for M tuberculosis via aninterferon-g immunogold enzyme-linked immuno-sorbent assay test has been developed, and thesetests were more specific and sensitive than routinetuberculin skin testing in immunocompromisedpatients.49

Routine blood chemistries should be obtainedbefore the onset of therapy, and a careful historyshould be taken, with a focus on risk factors fortuberculosis. A chest roentgenograph and skintesting with purified protein derivative should beobtained in all patients, and immunogold testingshould be considered for immunocompromisedpatients. If the testing is positive, alternative thera-pies should be considered. If anti-TNF agents areadministered to positive patients, treatment oflatent TB should commence before initiation oftherapy. We also recommend screening forchronic hepatitis B infection before initiatingtherapy, and any neurologic symptoms shouldraise concern about a possible demyelinationsyndrome. The administration of live virusesshould be avoided.

Toxicity and Monitoring of Immunosuppressive Therapy 571

Other Biologic Agents

RituximabRituximab is a humanized murine antibody to themembrane-bound cell surface CD-20 glycoproteinon B lymphocytes. Rituximab is administeredintravenously and has regulatory approval for thetreatment of CD-20-positive non-Hodgkinlymphomas and refractory RA, and it has alsobeen used to treat antineutrophil cytoplasmic anti-body (ANCA)-associated vasculitis. Antibodyresponses to recall antigens are dramatically lowerin patients treated with rituximab.50

Fatal infusion reactions have been reported butprimarily occur with the initial infusion.51,52 Serumsickness has been reported with rituximab treat-ment in a variety of autoimmune diseases.53–56 Inaddition, progressive multifocal leukoencephal-opathy, a rare, demyelinating disease of thecentral nervous system that results from reacti-vation of latent Jakob-Creutzfeldt virus, hasbeen linked to rituximab therapy in patientswith malignancy as well as patients withRA.57,58 Interstitial pneumonitis has been re-ported in several patients with non-Hodgkinlymphoma.59–61 Recovery of lung function hasbeen reported with ceasing rituximab treatmentand administering corticosteroids,59 but fatalcases have been reported.60,61 Frequent moni-toring of vital signs during infusions may beprudent, and clinicians should be vigilant forsigns of new infection, reactivation of latentinfections, and bowel perforation.62

ANTIMETABOLITE/CYTOTOXIC AGENTSAZA

AZA is a purine analog that is cleaved in vivo to itsactive antimetabolite, 6-mercaptopurine. Its mech-anisms of action remain unclear, but it suppressesdelayed hypersensitivity responses and cell-mediated cytotoxicity via its effects on purinemetabolism, which likely inhibit DNA and RNAsynthesis, and, consequently, protein synthesis.63

Recent investigations suggest that AZA and itsmetabolites induce T-cell apoptosis by binding tothe guanidine triphosphatase, Rac1.64 AZA andmercaptopurine are degraded in erythrocytesand the liver via oxidation or methylation.Mercaptopurine undergoes thiol methylationintracellularly via thiopurine methyltransferase(TPMT), which converts it to thiopurine analogs.Deficiency of this enzyme occurs in approximately1 in 300 individuals and may lead to severe myelo-suppression.65 Intermediate concentrations ofTPMT have been linked to severe side effectsrelated to AZA, and measuring TPMT activity

before initiating AZA therapy has been suggestedto reduce the likelihood of serious side effects.66

Common adverse reactions associated with AZAinclude leucopenia,67 pancreatitis,68 and hepa-titis.69 Thrombocytopenia, anemia, megaloblasticanemia, aplastic anemia, eosinophilia, myelodys-plastic syndrome, and fatal acute myeloid leukemiahave also been reported.67,70–72 The incidence ofhepatitis or pancreatitis for patients receiving AZAfor Crohn disease has been reported to rangefrom 4% to 17% for both side effects indepen-dently,73–75 and AZA treatments were discontinuedin approximately 10% to 20% of patients becauseof side effects.67,75 Other adverse reactions thathave been linked to AZA include skin rash,alopecia, nausea, vomiting, hypersensitivity reac-tions, muscle weakness, and interstitial pneumo-nitis/fibrosis. In addition, risk for lymphoma, skincancer, and infection may be increased.

Concomitant administration of allopurinol cangreatly increase the effect of AZA and the risk ofassociated toxicities.76 The use of angiotensin-converting enzyme inhibitors with AZA has beenassociated with myelosuppression,77 and patientsreceiving AZA may be at increased risk of infectionfrom administration of live virus vaccines. Inhibi-tors of TPMT (eg, mesalamine) can considerablyincrease the risk of myelosuppression and shouldbe avoided. Similarly, coadministration of otherinhibitors of purine metabolism (eg, mycopheno-late) is not recommended, and concomitantadministration of other potentially hepatotoxicagents, such as methotrexate (MTX), should alsobe avoided. Monitoring of complete blood counts(CBCs) has been recommended every 2 weeksfor the first 4 weeks and then monthly thereafter.78

Similarly, liver function testing has been recom-mended every 2 weeks for the first 4 weeks andthen monthly.78

Cyclophosphamide

Cyclophosphamide (CYC), a synthetic alkylatingagent, is chemically related to the nitrogenmustards and was originally developed for treat-ment of malignant tumors. It has antineoplasticand immunosuppressive properties and hasreceived regulatory approval for the treatment ofvarious hematologic and nonhematologic malig-nancies. It has a dose-dependent, bimodal effecton the immune system. High doses have beenshown to induce an antiinflammatory immunedeviation (ie, suppression of TH1 and enhance-ment of TH2 lymphocyte activity), affectCD4CD25(high) regulatory T cells, and establisha state of marked immunosuppression.79 It hasbeen used to treat various CTD-associated lung

Meyer et al572

diseases such as scleroderma80,81 and otherforms of interstitial lung disease (ILD).82,83 It hasalso been used as a standard treatment ofANCA-associated vasculitis.84

CYC is metabolized in the kidney and liver. Theliver converts CYC to the active metabolites aldo-phosphamide and phosphoramide mustard, whichcause cell death by binding DNA and therebyinhibiting DNA replication. CYC and its metabolitesare excreted via the kidney. CYC can be adminis-tered via either continuous daily dosage (oral) orintermittent intravenous (IV) pulse therapy. Forseveral conditions, which include ANCA-associated vasculitis84,85 and scleroderma-associated lung disease,80,81 the pulse therapyseems to be as effective as and less toxic thandaily oral regimens. One of the disadvantages ofIV pulse therapy is the associated cost and needfor support staff to administer IV CYC. One of theadvantages of pulse therapy is that individualdoses of the drug can be adjusted based on thepatient’s individual white blood cell (WBC) count.In one study, dosage adjustments were made inalmost one-third of visits.83 Regardless of themethod of administration (IV vs oral), the sameguidelines for monitoring apply.

Hemorrhagic cystitis and fibrosis of the urinarybladder can occur, and hematuria frequentlyoccurs. Although hemorrhagic cystitis is an infre-quent complication, it can be severe and lifethreatening. Bladder toxicity likely occurs fromthe CYC parent compound and several CYCmetabolites including acrolein. Measures that arerecommended to limit hemorrhagic cystitis includeingesting more than 3 L of water or other fluidsdaily. Sodium 2-sulfanylethanesulfonate (MESNA)binds acrolein and some other CYC metabolitesin the urinary bladder and can attenuate toxicity.81

A large, prospective study of patients with Wege-ner granulomatosis reported that hematuriaoccurred in a time- and dose-dependentmanner.86 Of 145 patients studied, 73 (50%)developed nonglomerular hematuria, 7 of whomhad bladder cancer. Hematuria occurred a medianof 37 months after initiating CYC. Overall, 15% ofthe patients developed hematuria within the firstyear of treatment. In the placebo-controlled trialof oral CYC versus placebo for scleroderma-associated lung disease, 9 of the CYC-treatedpatients developed hematuria versus 3 of theplacebo group.80

Bladder cancer is increased in individuals whohave received CYC, and cigarette smoking furtherincreases risk. Bladder cancer is also increased infrequency in CYC-treated patients who have hadhemorrhagic cystitis.86 Bladder cancer seems tobe dose and duration dependent, with at least

a 2-fold increased risk occurring with each 10 gof cumulative drug exposure,87 and furtherincreases occur over time after a total dose of20 g.86 Cancers have been known to occur manyyears following CYC cessation. Bladder cancerscreening with urinalysis seems to be sufficientto detect cancer as long as subjects with hema-turia receive additional evaluation.86

CYC may cause major bone-marrow suppres-sion, including leukopenia, anemia, and/or throm-bocytopenia. Leukopenia is a dose-relatedcomplication of the drug and can occur evenwith lower drug doses.88 In a randomized trialcomparing oral CYC versus placebo forscleroderma-associated pulmonary fibrosis, 19 of79 (24%) of CYC-treated patients developedleukopenia and 7 (9%) had neutropenia duringthe year of CYC therapy, whereas none of thepatients given placebo had any form of leuko-penia.80 Anemia was more common with CYC,but the difference from placebo was not signifi-cant. These rates are higher than those reportedfor intermittent IV CYC.81,83,84,89,90

Lymphomas, leukemias, skin cancers, andprobably other solid-organ malignancies are likelyincreased in frequency in individuals receivingCYC.91 In a retrospective study of long-termfollow-up of patients with Wegener granulomato-sis treated with CYC, increased cancer incidencewas seen for squamous cell skin cancer (oddsratio [OR] 5 7.3; 95% confidence interval [CI]4.4–12), leukemias (OR 5 5.7; 95% CI 2.3–12)and for malignant lymphomas (OR 5 4.2; 95% CI4.2–8.3).92 Many such studies are complicatedby some increase in cancer incidence with thebaseline disease state. In a Swedish registry studyof scleroderma, no increase in malignancy wasseen in 246 patients comparing CYC users withthose treated with other medications and followedfor up to 13 years.93 In a prospective 15-year eval-uation of 726 lung patients with lung cancertreated with busulfan, CYC, or placebo, no addi-tional malignancies were seen in the CYC armabove the placebo rate.94

CHF, hemopericardium, and hemorrhagicmyocarditis have been seen after high doses ofCYC. These side effects usually resolve after stop-ping therapy. Alopecia is common and hair mayreturn with a different texture or color. Skin rashesmay be seen and rare cases of toxic epidermalnecrolysis have been seen. The frequency ofbacterial, fungal, viral, and protozoan infectionsare increased on CYC. There is no consensusthat prophylaxis for any of these infections isnecessary in patients receiving CYC, althoughsome case series have used prophylaxis for pneu-mocystis jerocomia.

Toxicity and Monitoring of Immunosuppressive Therapy 573

Lung fibrosis has been a consistent finding inanimal studies of CYC use.95,96 However, thefrequency of this complication in humans hasbeen difficult to define in part because of the pres-ence of confounding variables such as concomi-tant use of other cytotoxic drugs, opportunisticinfections, diffuse pulmonary malignancy, radia-tion pneumonitis, and oxygen toxicity. Therefore,the literature is limited to case reports and smallcase series97 that suggest drug withdrawal withor without corticosteroids usually resolves earlymanifestations of this side effect. A large prospec-tive study in which 192 patients received CYCfailed to find any case of lung fibrosis in 5 yearsusing chest radiography.98

A CBC with platelets should be monitoredfrequently (at least every 2 weeks at initiation oftherapy) and is the most reproducible methodavailable for CYC dose adjustment. WBC countshould be kept greater than 2000 cells/mm3 andhigher WBC counts (eg, >4000 cells/mm3)decrease the incidence of infectious complica-tions. A urinalysis to evaluate for microscopichematuria should be obtained monthly beginningbefore initiation of therapy. Although hemorrhagiccystitis is an infrequent complication, it can besevere and life threatening and carries anincreased risk of bladder cancer. Because theseside effects are dose and time dependent, intermit-tent monitoring of urinalysis at least every 3 monthsis recommended. This complication is decreasedby fluid intake that should consist of a 3-L minimumdaily. If hemorrhagic cystitis has occurred ora greater than 10 g cumulative dose of CYC hasoccurred, urinalysis should be obtained yearlyand microscopic hematuria evaluated with morecomprehensive testing. Because CYC therapy,particularly if sustained over long periods,increases risk of developing urothelial tumors,urine cytology could be performed on a yearlybasis to facilitate early detection of bladder cancer.

MTX

MTX is approved in the United States for treatmentof RA, psoriasis, and several malignancies. It hasalso been used to treat pulmonary sarcoid-osis,99,100 and for induction and maintenancetherapy for Wegener granulomatosis 101,102 andfor ILD associated with polymyositis-dermatomyositis.103

MTX is converted to polyglutamates in the liver,and polyglutamate-mediated inhibition of extracel-lular adenosine metabolism is believed to accountfor its immunosuppressive effects.104,105 Theplasma half-life of MTX is only 8 to 15 hours, butits immunosuppressive actions can be measured

in peripheral blood cells ex vivo for up to 1 week.Adenosine receptor antagonists (eg, caffeine andtheophylline) have been shown to inhibit the antiin-flammatory effect of MTX in animal models.106

Major toxicities attributed to MTX include liverdamage, pneumonitis, and cytopenias. Nausea,diarrhea, fatigue, rash, headaches, cognitiveimpairment, and alopecia are also common sideeffects. Because most large, randomized clinicaltrials have monitored subjects for a maximum of1 to 2 years, the cumulative toxicity profile mayunderestimate the potential for adverse reactionsto occur with prolonged MTX treatment. Sideeffects have led to drug discontinuation in approx-imately 30% of subjects in clinical trials for RA andpsoriasis. Adverse reactions during MTX therapyfor RA included increase in transaminase levels(21%), nausea (18%), and diarrhea (12%),107 andadvanced age and/or impaired renal functionhave been identified as risk factors fortoxicity.108,109 In a British registry study of 673 indi-viduals prescribed MTX for long-term treatment ofrheumatologic diseases, side effects attributed toMTX led to discontinuation in 36.3%.110 Themost common reasons for discontinuing therapywere GI symptoms (10.8%), abnormal liver func-tion tests (5.5%), peripheral blood cytopenias(5.5%), pulmonary symptoms (3%), and cuta-neous abnormalities (2.1%). Life-threateningadverse events occurred in 1.7% of this patientcohort.

Pulmonary toxicity is a well-documented poten-tial side effect of MTX treatment,111–113 andpulmonary toxicity does not seem to be prevent-able with folic acid supplementation. Potentialpatterns of pulmonary toxicity include pneumo-nitis, bronchitis with airways hyperreactivity,pulmonary fibrosis, bronchiolitis obliterans withorganizing pneumonia, and diffuse alveolardamage. The most commonly reported manifesta-tion is hypersensitivity pneumonitis, which hasa reported incidence of 1% to 5%.114 Routinehigh-resolution computed tomography and/orserial pulmonary function tests have not beenshown to be useful in monitoring patients fortoxicity.115

Hepatic toxicity has also been reported with pro-longed MTX treatment. MTX was stopped in oneprospective study of patients with RA as a resultof hepatotoxicty in 5% of patients.110 Severehepatic toxicity is uncommon but may occur.Severe liver failure and cirrhosis was detected in24 patients in this large cohort of patients withRA; the cumulative incidence was 1 per 1000patients.110 Roenigk and colleagues116 have devel-oped a histologic classification (grade 0–IV) toassess MTX toxicity, and a meta-analysis of

Meyer et al574

636 total patients with RA or psoriasis from 15 pub-lished studies concluded that 28% of patients pro-gressed at least one grade while on therapy.117 Fivepercent of the patients had advanced liver disease(grade IIIB or IV), and the major risk factors fordeveloping liver damage included a large cumula-tive dose of MTX, heavy alcohol use, and under-lying psoriasis. Patients had a 6.7% chance ofprogressive liver damage for each cumulativegram of MTX. These data led to the recommenda-tion that liver biopsy should be considered aftereach 1 to 1.5 g of cumulative MTX.116 However,monitoring liver function tests on a regular basisfor patients with RA has been found to be sufficientto screen for potential MTX-associated livertoxicity,118 which may be because of a lower inci-dence rate of severe liver toxicity in patients withRA versus patients with psoriatic arthritis.119

Duration of exposure to MTX likely accounts fora substantial proportion of its toxicity. Therefore,once-weekly regimens are favored, and lead tofewer side effects. Delayed clearance of themedication (because of renal insufficiency, thepresence of third-space effusions, or GI obstruc-tion) leads to prolonged circulating MTX levelsand increases the risk of toxicity.120–122 Risk formany of the bothersome side effects can be mini-mized by using folic acid. Typical doses are 1 to 2mg/d, although daily doses up to 5 mg have beendescribed. Because MTX is a dihydrofolatereductase inhibitor, folic acid supplementationmay bypass the MTX-induced blockade of nu-cleic acid synthesis. A well-designed randomizedtrial of folic acid supplementation versus placeboin RA patients showed that MTX at 5 mg or 27.5mg/wk with folate supplementation had no effecton drug efficacy in patients with RA, but it signif-icantly reduced toxicity scores for both doses.123

A second, larger study (n 5 434) in patients withRA reported similar results; MTX-related toxicityled to discontinuation in 38% of placebo-treatedsubjects versus 17% of those taking 1 to 2 mgof folic acid daily and had no effect onefficacy.124

Patients on MTX should undergo routine CBCsand renal function,125,126 and the dose of MTXshould be adjusted if leukopenia is detected. Inone study, 26% of patients had one or more hema-tologic abnormality. More than 95% of thesecases had symptoms consistent with viral infec-tion, and the observed abnormality resolved withina month of withholding MTX and did not recur withrechallenge.127 Liver function, especially the trans-aminases, should also be monitored, with routineliver function testing usually performed every 4 to12 weeks while the patient is taking thedrug.118,126,128 Liver biopsies to monitor for

irreversible hepatotoxicity (eg, after every 1–2cumulative grams) have been recommended bysome,116 but liver biopsies are no longerrecommended by the American College of Rheu-matology (ACR).118 The current ACR recommen-dation is to monitor transaminases. Iftransaminase levels show a sustained increase,biopsy is then recommended.118 Monitoringexclusively with peripheral blood transaminaselevels only may miss an occasional patient withadvanced liver disease.129 Patients should beasked about nausea, diarrhea, and stomatitis. Ifpresent, these side effects usually respond todose reduction and the addition or increase indosage of 1 mg folic acid.123

Leflunomide

Several large clinical trials led to regulatoryapproval of leflunomide for treatment of RA,130–133

and clinical trials have been reported for psoriasisand psoriatic arthritis, Sjogren syndrome,systemic lupus erythematosis, ankylosing spondy-litis, and Wegener granulomatosis.130,132,134–138 Itsuse has also been described for antisynthetasesyndrome, relapsing polychondritis, adult-onsetStill disease, and scleroderma.139–142 It antago-nizes T- and B-lymphocyte activation and prolifer-ation by inhibiting de novo pyrimidine synthesis.143

Leflunomide is metabolized in the liver and bowelwall to an active metabolite that is primarily elimi-nated via the biliary tract, although some renalexcretion also occurs.144 It undergoes extensiveenterohepatic recirculation, with an eliminationhalf-life of approximately 2 weeks.

The most common side effects reported incontrolled trials include nausea, diarrhea,alopecia, hypertension, increased liver enzymes,and rash. These side effects seem to be doserelated, and often resolve with dose reduction.Postmarketing experience has shown rareinstances of serious infection, cytopenias, angioe-dema, fulminant hepatitis, interstitial pneumonitis,peripheral neuropathy, and severe dermatologicsyndromes (Stevens-Johnson syndrome,erythema multiforme, toxic epidermal necrolysis).However, postmarketing data are severely limitedby ascertainment bias, concomitant immunosup-pressive use, and the presence of the underlyingdisease; therefore, attribution of these toxicitiesto leflunomide remains unclear. Although lefluno-mide increases renal excretion of uric acid anddecreases tubular reabsorption of phosphate,145

clinically significant hypophosphatemia was notidentified in a large clinical trial.131

Hepatic toxicity generally occurs within the first6 months of therapy, and it is more common in

Toxicity and Monitoring of Immunosuppressive Therapy 575

patients with preexisting liver dysfunction or whenconcomitantly treated with MTX.146 Increases ofalanine aminotransferase levels greater than 3times the upper limits of normal were observedin 2% to 4% of patients in clinical trials for treat-ment of RA,130,131,133 and these usually normalizedwith dose adjustment or discontinuation of thedrug. The incidence of hepatocellular necrosisseems to be 100-fold less than for increases intransaminase levels.147 When used in combinationwith MTX, increases in liver function tests occurmore frequently in the absence of folic acidsupplementation.

Peripheral neuropathy has been reported 148,149

and occurred in a range of 3 days to 3 yearsfollowing initiation of therapy. The neuropathyassociated with leflunomide may be caused byperineural vasculitis,148 and outcome is best ifleflunomide is stopped soon after symptom onset.A recent, controlled, prospective clinical trial re-ported neuropathic symptoms in 54% versus 8%of patients with RA treated with other disease-modifying agents.150 When severe neuropathyoccurs, administration of oral cholestyramine(see later discussion) is recommended in additionto discontinuing the drug.150 Several cases ofinterstitial pneumonitis have been reported,151–153

some of which have been fatal. However, thesedata are confounded by the frequent associationof ILD and RA combined with physician preferenceto treat patients with CTD-associated ILD with le-flunomide versus MTX.153

A CBC, liver function panel, phosphate, andcreatinine tests are recommended before startingleflunomide therapy and they should be repeatedevery 4 to 6 weeks for the first 6 months of treat-ment. If stable, these parameters can be checkedevery 6 to 12 weeks beyond 6 months. Clinicalmonitoring for infection and signs of hepatoxicityshould continue throughout the course of therapy,and laboratory examinations should be performedevery month indefinitely if leflunomide is coadmi-nistered with MTX. If serious toxicity develops,elimination of the active metabolite may be neces-sary. Cholestyramine at 8 g 3 times daily is recom-mended because of the enterohepaticrecirculation of leflunomide. Activated charcoal,although not so palatable as cholestyramine, isan acceptable alternative.

Mycophenolate

Mycophenolic acid (MPA) selectively and potentlyinhibits T- and B-lymphocyte proliferation by inhib-iting the de novo purine pathway,154 and it hasregulatory approval for the prophylaxis of organrejection in cardiac, liver, and renal transplantation

in combination with cyclosporine and corticoste-roids. MPA has been used to treat lupusnephritis,155 RA,156 Wegener granulomatosis,157

systemic lupus erythematosus,158 and pulmonarydisease associated with various collagen vasculardisorders.159

Two forms of mycophenolate are currently avail-able for prescription.160 Mycophenolate mofetil(MMF), which is administered orally, is the mor-pholinoethyl ester prodrug of MPA, and it is rapidlyhydrolyzed (within 5 minutes) in the GI tract toMPA. Mycophenolate sodium is a delayed-release enteric formulation of MPA. MPA mayaccumulate in end-state renal failure, requiringhemodialysis or peritoneal dialysis, and doseattenuation may be required. MPA is extensivelyconjugated to glucuronide, which is predominantlycleared via renal excretion, and MPA pharmacoki-netics do not seem to be altered in patients withhepatic dysfunction.161 Cardiovascular (systemichypertension, peripheral edema, tachycardia),dermatologic (rash, neoplasm), endocrinologic(hyperglycemia, cushingoid change, hirsutism),metabolic (hypercholesterolemia, hypophospha-temia, hypokalemia, hyperkalemia), GI (nausea,anorexia, vomiting, abdominal pain, diarrhea, con-stipation), hematologic (anemia, red blood cellaplasia, leukopenia, thrombocytopenia, leukocy-tosis), infectious (opportunistic infection), muscu-loskeletal (bone pain, myalgias, cramps),neurologic (headache, tremor, insomnia, dizzi-ness, anxiety), ocular (blurred vision, cataracts,blepharitis, keratitis, glaucoma, macular abnor-malities), genitourinary (infection, hematuria,tubular necrosis, urinary frequency, burning onurination, kidney stones, vaginal burning, vaginalbleeding), and respiratory (cough, dyspnea, infec-tion, pneumonitis, fibrosis) abnormalities have allbeen associated with MPA administration. Myco-phenolate usually lacks a significant effect onhematopoiesis and neutrophil populationsbecause other cell types (nonlymphocytic) canuse salvage pathways to obtain guanine.However, neutropenia can occur and may respondto simple modification of mycophenolatedosage.162

Several drug interactions can occur with myco-phenolate.163 Activated charcoal, aluminum ormagnesium salts, cholestyramine, colesevalam,colestipol, or iron can inhibit absorption from theGI tract.164 Mycophenolate should not be coad-ministered with AZA because of increased inhibi-tion of purine metabolism, and mycophenolatecan increase plasma concentration of acycloviror ganciclovir, especially when renal impairmentis present. Mycophenolate may decrease expo-sure to hormonal therapies, and live attenuated

Meyer et al576

virus vaccines should not be given concomitantlywith MPA. Patients receiving MPA may have aninadequate immunologic response tovaccination.165

CBCs have been recommended on a weeklybasis for the first month, twice monthly for thesecond and third months of treatment, and thenonce a month for the remainder of the first yearof treatment. However, when mycophenolate isnot given together with other agents that cansynergistically depress bone-marrow function,such as calcineurin inhibitors, obtaining CBCs onsuch a frequent schedule is probably not neces-sary. Plasma levels of MPA can be used to guidetherapy as well as to detect toxicity.166,167 In addi-tion, MPA serum concentrations may be useful inpatients with impaired renal function to preventtoxicity caused by high levels and graft rejectioncaused by low levels.168 However, it has notbeen conclusively shown that monitoring levelsminimizes toxicity or risk for rejection.169,170

OTHER AGENTSChloroquine/Hydroxychloroquine

Chloroquine and hydroxychloroquine are synthetic4-aminoquinoline antimalarial agents that haveantiinflammatory properties.171 Chloroquine iswell absorbed from the GI tract and rapidly ab-sorbed from subcutaneous and intramuscularsites. Chloroquine is sequestered in varioustissues (lung, liver, spleen, kidney, melanin-containing tissues, brain, and spinal cord).171 Therates of absorption and elimination are closelybalanced for orally administered drug. Peak chlo-roquine plasma levels are reached 3 to 5 hoursafter oral administration. The half-life of chloro-quine has been reported to increase with sus-tained drug administration. Its half-life has beenreported to begin at 30 to 60 days and can extendfor years, and prolonged half-lives have beenreported with sustained and prolongedadministration.171,172

Prolonged therapy with chloroquine or hydroxy-chloroquine can cause toxic myopathy, cardiomy-opathy, and peripheral neuropathy; thesereactions improve if the drug is promptly with-drawn.173,174 Cardiovascular effects may progressthrough vasodilation, hypotension, suppressedmyocardial function, cardiac arrhythmia, andcardiac arrest. Central nervous system effectsmay progress through confusion, convulsions,and coma. Oral therapy may cause GI upset,headache, visual disturbances, urticaria, andpruritus. Prolonged treatment may cause head-ache, blurring of vision, diplopia, confusion,convulsions, lichenoid skin eruptions, bleaching

of the hair, and electrocardiographic abnormalitiessuch as widening of the QRS interval and T-wavechanges. These side effects usually reverse withdiscontinuation of therapy. Chloroquine may alsocause discoloration of the nail beds and mucousmembranes and may also interfere with selectedvaccines.175–177 When chloroquines are used aschronic therapy for inflammatory disorders, irre-versible retinopathy and ototocity may occur withhigher oral doses if in excess of 250 mg/d.178–180

Because hydroxychloroquine may cause lessocular toxicity than chloroquine,180 hydroxychlor-oquine has been preferred to chloroquine for treat-ing inflammatory disorders. In addition to intervalevaluations of patients on chronic therapy toscreen for adverse drug reactions, routine ocularscreening has been recommended for patientsreceiving antimalarial agents with a frequency ofevery 6 to 12 months.181

Imatinib Mesylate

Imatinib mesylate, a protein-tyrosine kinase inhib-itor, inhibits cellular proliferation and inducesapoptosis in a variety of abnormal cell lines. Ithas received regulatory approval for the treatmentof chronic myeloid leukemia and GI stromal tumor.In addition to suppressing the specific kinasedysfunction created by the gene mutations forthose malignancies, imatinib inhibits receptor tyro-sine kinases for platelet-derived growth factor(PDGF) and stem cell factor (SCF), and it inhibitsPDGF- and SCF-mediated cellular events. Imati-nib has been used in fibrotic lung diseases andpulmonary arterial hypertension.182–184

Imatinib has high oral bioavailability (98%), andthe parent and active N-desmethyl derivative arecleared predominantly via hepatic CYP3A4enzymes. Bullous dermatologic reactions(including erythema multiforme and Stevens-Johnson syndrome), significant fluid retention, GIcomplications, and hematologic abnormalitieshave been reported.185–187 Fluid retention (whichcan manifest as pleural effusions, ascites, pulmo-nary edema, or peripheral edema) occurs morefrequently in patients older than 65 years. Neutro-penia, anemia, and thrombocytopenia have beenlinked to imatinib therapy, and the package insertrecommends a CBC weekly for the first month,biweekly for the second month, and periodicallythereafter as clinically indicated.

Hepatic impairment, which can be severe, hasbeen reported. Liver function testing (transami-nases, bilirubin, and alkaline phosphatase) is rec-ommended at baseline and then monthly and/oras clinically indicated per the package insert.Available data are insufficient to determine if

Toxicity and Monitoring of Immunosuppressive Therapy 577

lymphoma or nonlymphomatous malignancies areincreased, although some carcinogenesis, muta-genesis, and impairment of fertility studies aresuggestive. Drug-induced pneumonitis has beenreported,188,189 but only dyspnea has been re-ported in randomized clinical trials for treatmentof malignancies. Peripheral edema may occur,especially in elderly patients, and can be managedwith diuretic therapy.

DRUG-DRUG INTERACTIONS

Numerous drug-drug interactions may occur,especially with use of the nonbiologic agents.These interactions are summarized in Table 4.Drug-drug interactions must be considered whennew drugs are administered as well as when coad-ministered drugs are withdrawn or doses arealtered, which is particularly important for drugsthat are metabolized by the cytochromeP-450CYP3A4 enzyme system. Drug levels ofCYP3A4-metabolized agents (eg, imatinib) canbe significantly increased by administration ofdrugs that are also metabolized via this pathwayor reduced by coadministration of CYP3A4inducers. Appropriate dose adjustment and moni-toring should be observed if a CYP3A4 drug isadministered and inhibitors or inducers of thisenzyme are coadministered. Many commonlyprescribed agents (eg, imidazole antifungalagents, macrolide antibiotics) can significantlyaffect blood levels of the CYP3A4-metabolized im-atinib mesylate. In addition, most of the agentscovered in this article can suppress antibodyresponses to vaccines. In addition, recipientsmay be endangered if live virus vaccines are givenwhile the patients are receiving pharmacologicimmunosuppression. Potentially significant inter-actions have been documented for some of theseagents with ingested substances such as grape-fruit juice, echinacea, and herbal preparations orsupplements. Patients should be aware of thesepotential interactions.

PREGNANCY

All of the nonbiologic immunosuppressive agentsmay have teratogenic or embryocidal effects onthe fetus and have been placed in the US Foodand Drug Administration (FDA) categories of C,D, or X; none has been assigned to category A(Table 5).190 CYC is teratogenic during pregnancy(FDA category D), and it should not be given towomen with childbearing potential withoutadequate measures to prevent pregnancy.However, CYC has been administered success-fully during the third trimester when considered

necessary to control severe disease requiringtreatment. Men should not father a child duringCYC therapy or for a few months followingcessation of CYC administration. Because post-treatment sterility may occur in men or womenduring treatment with CYC, consideration shouldbe given before treatment to bank sperm oroocytes if future pregnancy is desired. MTX andthe anti-TNF agents have been shown to bedirectly toxic to the fetus,190 as has mycopheno-late. AZA has, however, been given throughoutthe course of successful pregnancies.191,192

However, pregnancy should be discouraged andavoided when patients are taking these medica-tions, and these agents should not be prescribedfor pregnant women unless the treatment benefitclearly outweighs the risk of teratogenic effectson the developing fetus.

PEDIATRIC DOSING

There are limited data on the use of immunosup-pressive drugs for the treatment of inflammatorydisorders in children. Antimalarial agents havebeen used to treat rheumatologic diseases in chil-dren for many years, and these drugs are generallyfelt to be safe despite limited published literature.Toxicities for older children are generally believedto parallel those for adults. However, this maynot be the case for certain situations. Pharmacoki-netic parameters and mycophenolate levels werefound to be similar for adults and children in onestudy, but mycophenolate levels were dispropor-tionately increased in children when kidney func-tion was impaired and/or albumin levels weredepressed.193 Pharmacokinetic monitoring in chil-dren receiving MTX revealed that the maximumdose appeared to be 10 mg/m2 for children anddiffered from dosing for adult patients.194 In addi-tion, newer approaches to treating children withimmunosuppressive therapies are evolving inwhich certain agents, such as corticosteroids,are minimized.195,196 Monitoring strategies mayalso be helpful in children to help avoid toxicityfrom some drugs. Monitoring metabolite levels inpatients treated with AZA may help to minimizetoxicity and enhance treatment efficacy.197

MONITORING AND PREVENTIONOF TOXICITY

Specific recommendation for pretherapy evalua-tion and monitoring of clinical and laboratoryparameters during therapy are given in Table 3for the various drugs. Reactivation of latent infec-tion (eg, tuberculosis, herpesviruses, endemicfungi) or the onset of new infection (eg,

Table 4

Summary of drug-drug interactions

Specific Drug

Metabolized

by CYP3A4)

Imidazole

Antifungal

Agents

Psychiatric

Therapies

Antibacterial

Agents

Steroidal

Therapies

Antiarrythmic

Therapies

Anticon-

vulsants Vaccines

Anakinra/

MTX/Myco-

phenolate/

AZA NSAIDs

ACE

Inhibitors

Thiazide

Diuretics

GI Acid

Reducers

(Proton Pump

Inhibitor; H-2,

Elements) Allopurinol Coumadin

Hydroxymethyl-

glutaryl

Coenzyme

A Reductase

Inhibitors

Herbal

Supplements

Adalimumab 1 1

Etanercept 1 1

Infliximab 1 1

AZA 1 1 1 1 1 1

Cyclophos-

phamide

1 Chloram-

phenicol

1 1 1 1 1 1 1

Leflunomide Rifampin

Rifapentine

1 1 1

MTX Penicillins,

Doxycyline

1 1 1 1 1 1 1

Mycophenolate Norfloxacin 1 1 1 1 1

Chloroquines 1 Quinolones

Trimethoprim

sulfa/Sulfa

macrolides

Pentamidine

1 1

Imatinib

mesylate

1 1 Macrolides

Rifampin

Rifabutin

Rifapentine

1 1 1 1 1

Rituximab 1 1

CYP3A4-metabolized drugs (competitors; increased levels of other drugs metabolized by CYP3A4): nefazodone, macrolides, imidazoles, metronidazole, cisapride, cimetidine, chloramphenicol, grapefruit juice, calcium channel-blockers,

theophylline. CYP3A4 inducers (decreased drug level caused by increased activity of CYP3A4): phenytoin, phenobarbitol, modafinil, carbamazepine, quinopristine, rifampin, sulfasalazine, sulfinpyrazone.

578

Table 5Effects on pregnancy and pregnancy classification

Specific Drug

Pregnancy Category

Category Definitions (FDA)FDA(United States) Australia

PrednisoneMethyprednisolone

None A A. Controlled studies in women fail to show a risk to the fetus in the first trimester (and there is noevidence of a risk in later trimesters), and the possibility of fetal harm seems remote

B. Either animal-reproduction studies have not shown a fetal risk but there are no controlled studies inpregnant women or animal-reproduction studies have shown adverse effect (other than a decrease infertility) that was not confirmed in controlled studies in women in the first trimester (and there is noevidence of a risk in later trimesters)

C. Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal orother) and there are no controlled studies in women, or studies in women and animals are notavailable. Drugs should be given only if the potential benefit justifies the potential risk to the fetus

D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may beacceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a seriousdisease for which safer drugs cannot be used or are ineffective)

X. Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence offetal risk based on human experience or both, and the risk of the use of the drug in pregnant womenclearly outweighs any possible benefit. The drug is contraindicated in women who are or may becomepregnant

Adalimumab B CEtanercept B BInfliximab B NoneAZA D DCyclophosphamide D DLeflunomide X NoneMTX X DMycophenolate D DChloroquines C DImatinib D DRituximab C C

579

Meyer et al580

aspergillosis, histoplasmosis, other endemic fungi,pneumocystis pneumonia, cytomegalovirus pneu-monia, viral hepatitis) during the course of treat-ment presents significant risks for patientsundergoing intensive pharmacologic immunosup-pression. Infection may occur because ofsuppression of immune cell function (eg,T lymphocytes), bone-marrow toxicity with neutro-penia, or a combination of depressed cell functionand decreased numbers of immune effector cells.Pneumocystis pneumonia may complicate thecourse of patients with systemic autoimmunedisease who are treated with intense immunosup-pression.198–200 If intensive immunosuppressivetherapy is prescribed, prophylaxis for P jirovecishould be strongly considered.201,202 Althoughscreening for active or latent tuberculosis is sup-ported only by the literature for anti-TNF therapy,the administration of other potent immunosup-pressive regimens could lead to reactivation oflatent infection. Ideally, patients should beuniformly and carefully screened for evidence ofactive or latent tuberculosis before the initiationof any intense immunosuppressive therapies.

Many of the nonbiologic agents can significantlydepress bone-marrow function. Granulocytic celllines are most susceptible, and neutropenia maycomplicate therapy by predisposing patients toinfection. Other hematopoietic cell lineages mayalso be affected and lead to anemia or thrombocy-topenia. Other drugs (eg, trimethoprim sulfa organciclovir) given for prophylaxis or treatment ofinfection may contribute to bone-marrow suppres-sion and potentiate the effect of immunosuppres-sive drug therapies. Intermittent monitoring ofbone-marrow function via CBC with differentialcell count is advised for all patients receiving drugsthat are associated with potential bone-marrowsuppression.

GI toxicity including severe hepatotoxicity canoccur as a consequence of several nonbiologicagents. MPA derivatives can significantly affectintestinal transit times and often cause diarrhea,which can be severe in some instances and notnecessarily correlate well with mycophenolateblood levels. Although blood levels of mycopheno-late are not routinely obtained to monitor thisagent, a level can be obtained if diarrhea compli-cates therapy, and a high level would implicatemycophenolate as a potential cause of thiscomplication if other causes such as infectionare excluded. Serious hepatic injury can occurwith MTX, AZA, or leflunomide, and hepatic func-tion should be intermittently monitored (eg, oncemonthly) with appropriate testing while patientsare receiving agents that can potentially causeserious hepatotoxicity.

Patient education is an important aspect ofmonitoring for infection and other adverse drugreactions. Patients need to be informed of theincreased risk of infection and report in a timelyfashion symptoms such as fever, new onset orchange in cough, or shortness of breath. Becausemany of the noncorticosteroid drugs discussedearlier may be pneumotoxic,97,114,151,152,203–206

increasing dyspnea or other respiratory symptomsshould be reported promptly. In addition, patientsneed to be aware that taking new medications maylead to significant drug-drug interactions, and theyshould question the possibility of drug interactionswhenever a change in their medications is madewhile they are on therapy with the noncorticoste-roid agents discussed earlier.

SUMMARY

Immunosuppressive drug therapy for systemicautoimmune disorders considerably increasesthe risk of infection and various other complica-tions that range from bone-marrow suppressionand hepatic dysfunction to pulmonary toxicity.Provider knowledge of potential adverse reactionsto these drugs combined with the use of strategiesfor pretherapy screening before drug administra-tion plus appropriate interval clinical evaluationand laboratory testing while on therapy are keyto avoiding severe complications of immunosup-pressive drug therapy. In addition, patient educa-tion is important, and prophylactic measures toprevent complications (eg, administration of folicacid, trimethoprime-sulfa prophylaxis, appropriatescreening and treatment of osteopenia/osteopo-rosis) can benefit the patient.

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